1. Field of the Invention
This invention relates to microporous membranes, and more particularly to cationic charge modified microporous membranes suitable for the filtration of aqueous fluids, such as biological liquids.
2. Prior Art
Microporous membranes are well known in the art. For example, U.S. Pat. No. 3,876,738 to Marinaccio et al (1975) describes a process for preparing a microporous membrane, for example, by quenching a solution of a film forming polymer in a non-solvent system for the polymer. European Patent Application 0 005 536 to Pall (1979) describes a similar process.
Other processes for producing microporous membranes are described, for example, in the following U.S. Pat. Nos.:
3,642,668 to Bailey et al (1972); PA1 4,203,847 to Grandine, II (1980); PA1 4,203,848 to Grandine, II (1980); and PA1 4,247,498 to Castro (1981). PA1 3,497,451 to Hoehn et al (1970)--the use of "type 8" nylon for the desalination of sea water; PA1 3,615,024 to Michaels (1968)--an anisotropic reverse osmosis membrane which may be nylon; PA1 4,148,606 to Morita et al (1979)--a method of sterilizing a dialyzer by irradiating the semipermeable membrane in the presence of an antibacterial agent; and PA1 4,176,156 to Asanuma et al (1979)--a method for heat sterilizing an artifical kidney.
Commercially available microporous membranes, for example, made of nylon, are available from Pall Corporation, Glen Cove, N.Y. under the trademark ULTIPOR N.sub.66. Another commercially significant membrane made of polyvinylidene fluoride is available from Millipore Corp., Bedford, Mass. under the trademark Durapore. This membrane is probably produced by the aforementined Grandine, II patents. Such membranes are advertised as useful for the sterile filtration of pharmaceuticals, e.g. removal of microorganisms.
Various studies in recent years, in particular Wallhausser, Journal of Parenteral Drug Association, June, 1979, Vol. 33, #3, pp. 156-170, and Howard et al, Journal of the Parentral Drug Association, March-April, 1980, volume 34, #2 pp. 94-102, have reported the phenomena of bacterial break-through in filtration media, in spite of the fact that the media had a low micrometer rating. For example, commercially available membrane filters for bacterial removal are typically rated as having an effective micrometer rating for the microreticulate membranes structure of 0.2 micrometers or less, yet such membrane typically have only a 0.357 effective micrometer rating for spherical contaminant particles, even when rated as absolute for Ps. diminuta, the conventional test for bacterial retention. Thus passage of a few microorganisms through the membrane may be expected under certain conditions and within certain limits. This problem has been rendered more severe as the medical uses of filter membranes increases.
Brown et al highlights this problem in CRC Critical Reviews in Environment Control, March 1980, page 279 wherein increased patient mortality and morbidity derived from contamination of sterile solutions for topical, oral, and intravenous therapy are reported.
One method of resolving this problem and its inevitable consequences, is to prepare a tighter filter, i.e. one with a sufficiently small effective pore dimension to enable the capture of microorganisms, bacterial pyrogen and viral contaminants, by mechanical sieving. Such filter structures, in the form of microporous membranes of 0.1 micrometer rating or less, may be readily prepared. The flow rates, however, exhibited by such structures at conventional pressure drops are prohibitively low. Generally, increasing the pressure drop to provide the desired flow rate is not feasible, even with costly replacement or modification of existing pumping equipment, due to the fact that pressure drop is an inverse function of the fourth power of pore diameter. Thus such modification of the internal geometry, i.e. pore size, of the microporous membrane is not an economical solution to the problem of bacterial breakthrough.
It has long been recognized that adsorptive effects can enhance the capture of particulate contaminants. For example, Wenk in his article "Electrokinetic and Chemical Aspects of Water Filtration", Filtration and Separation, May/June 1974, indicates that surfactants, PH, and ionic strength may be used in various ways to improve the efficiency of a filter by modifying the charge characteristics of either the suspension, filter or both.
It has also been suggested that adsorptive sequestration, i.e. adsorptive capture of particles by entry into and capture within the pore channels, may in some cases be more important to so-called sterile filtration than bubble point characterization of internal geometry (representing the "largest pore"). Tanny et al, Journal of the Parenteral Drug Association, November-December 1978, Vol. 21, #6 pp. 258-267 demonstrated that adsorptive effects to dominate the filtration of flu vaccine through membranes of mixed cellulose esters, cellulose triacetate, and vinyl chlorideacrylonitrile copolymer, counter to the then common understanding of filtration as involving particulate removal by sieve-retention. This is consistent with the observation that bacterial pyrogen and virus particles may be removed by filtration through a membrane even though they are smaller than the pore sizes of commonly used 0.22 micrometer filters. Tanny et al, Journal of the Parenteral Drug Association, January-February, 1979, Vol. 33, #1, pp. 40-51.
Lukaszewicz et al, Journal of the Parenteral Drug Association, July-August, 1979, Vol. 33 #4, pp. 187-194, expanded on the foregoing and indicated that adsorptive particle arrest was a complex pheomenon. In discussing the effect of solution ionic strength on adsorptive particle arrest, Lukaszewicz et al indicated that high ionic strength tends to decrease adsorption, (thus reducing capture efficiency) if the attractive forces are due to electro-static interactions, i.e. the charge on the wall is opposite the charge on the particle.
Pall et al, Colloids and Surfaces 1 (1980), pp. 235-256, indicates that if the zeta potential of the pore walls of a membrane, e.g. nylon 66, and of the particles are both low, or if they are oppositely charged, the particle will tend to adhere to the pore walls, and the result will be removal of particles smaller than the pores of the filter. Pall et al, however, suggests the use of membranes of substantially smaller pore size to increase the probability of obtaining microbial sterility in filtering fluids.
Zierdt, Applied and Environmental Microbiology, December 1979, pp. 1166-1172, found a strong adherence by bacteria, yeast, erythrocytes, leukocytes, platelets, spores, and polystyrene spheres to membrane materials during filtration through membranes with pore-size diameters much larger than the particles themselves. Zierdt attributed this phenomena to electrostatic forces. The phenomena was partially blocked by pre-treating the filter membrane with a nonionic surfactant. Zierdt found that cellulose membranes adsorbed more bacteria, blood cells and other particles then did polycarbonate filters. Of lesser adsorptive capacity were vinyl acetate, nylon, acrylic, and Teflon membranes. Zierdt additionally found that solvent cast membrane filter materials, e.g. nylon had strong surface charges, whereas ordinary fibrous cellulose materials which are not solvent cast do not. Zierdt suggested that the development and manufacture of special purpose filter materials with more intrinsic charge than those currently available would extend the usefulness of this phenomenon. Conversely, manufacturing techniques could be developed that would build less intrinsic charge into filters when adsorption is not desired.
Attempts to increase the short life of filter media due to pore blockage and enhance flow rates through filter media having small pores have been made by charge modifying the media by various means to enhance capture potential of the filter. For example, U.S. Pat. Nos. 4,007,113 and 4,007,114 to Ostreicher, describe the use of a melamine formaldehyde cationic colloid to charge modify fibrous and particulate filter elements; U.S. Ser. No. 147,975 filed May 8, 1980, now U.S. Pat. No. 4,305,782, to Ostreicher et al describes the use of an inorganic cationic colloidal silica to charge modify such elements; and copending U.S. Ser. No. 164,797 filed June 30, 1980, now abandoned to Ostreicher et al, describes the use of a polyamido-polyamine epichlorhydrin cationic resin to charge modify such filter elements. None of these references teach or suggest charge modifying an organic polymeric microporous membrane, nor do any of the filtration media described therein, e.g. fiber and/or particulate, provide the advantages of such a membrane.
Similarly, U.S. Pat. Nos. 3,242,073 (1966) and 3,352,424 (1967) to Guebert et al, describe the removal of micro-organisms from fluids by passing the fluids through a filter medium which comprises a conventional anionic type filter aid, e.g., datomaceous earth, paper filter pulp, fullers earth, charcoal, etc., having an adsorbed cationic, organic, polyelectrolyte coating. The coated filter aid media is said to possess numerous cationic sites which are freely available to attract and hold particles bearing a negative surface charge.
U.S. Pat. No. 4,178,438 to Hasse et al (1979) describes a process for the purification of industrial effluent using cationically modified cellulose containing material. The cellulose containing materials are, for example, bleached or unbleached pine sulphite cellulose, kraft sulphate cellulose, paper, cardboard products, textiles fibers made of cotton, rayon staple, jute, woodfibers, etc. The cationic substituent is bonded to the cellulose via a grouping of the general formula --O--CH.sub.2 --N--, wherein the nitrogen belongs to an amide group of the cationic part and the oxygen to the cellulose part.
There are numerous references which describe the treatment of porous membranes for various objects. U.S. Pat. No. 3,556,305 to Shorr (1971) describes a tripartite membrane for use in reverse osmosis. The membrane comprises an anisotropic porous substrate, an ultra-thin adhesive layer over the porous substrate, and a thin diffusive membrane formed over the adhesive layer and bound to the substrate by the adhesive layer. The anisotropic porous membranes used in Shorr are distinguished from isotropic, homogeneous membrane structures whose flow and retention properties are independent of flow direction. Such isotropic membranes do not function properly when utilized in the invention of Shorr.
U.S. Pat. No. 3,556,992 to Massuco (1971) describes another anisotropic ultra-filtration membrane having thereon an adhering coating of irreversibly compressed gell.
U.S. Pat. No. 3,808,305 to Gregor (1974) describes a charged membrane of macroscopic homogeneity prepared by providing a solution containing a matrix polymer, polyelectrolytes (for charge) and a cross-linking agent. The solvent is evaporated from a cast film which is then chemically cross-linked. The membranes are used for ultrafiltration.
U.S. Pat. Nos. 3,944,485 (1976) and 4,045,352 (1977) to Rembaum et al describe ion exchange hollow fibers produced by introducing into the wall of the pre-formed fiber, polymerizable liquid monomers. The monemers are then polymerized to form solid, insoluble, ion exchange resin particles embedded within the wall of the fiber. The treated fibers are useful as membranes in water-treatment, dialysis, and generally to separate ionic solutions. U.S. Pat. No. 4,014,798 to Rembaum (1977) describes similar type hollow fiber using different type resins to produce the ion exchange mechanism.
U.S. Pat. No. 4,005,012 to Wrasidlo (1977) describes a process for producing a semi-permeable anisotropic membrane useful in reverse osmosis processes. The membranes are prepared by forming a polymeric ultra-thin film, possessing semi-permeable properties on a microporous support. Such an ultra-thin film may be formed by contacting an amine modified polyepihalohydrin with a polyfunctional agent and depositing this film on the external surface of a microporous substrate. Preferred semipermeable membranes are polysulfone, polystyrene, cellulose butyrate, cellulose nitrate and cellulose acetate.
U.S. Pat. No. 4,125,462 to Latty (1978) describes a coated semi-permeable reverse osmosis membrane having an external layer or coating of a cationic polyelectrolyte preferably poly (vinylimidazoline) in the bi-sulfate form.
U.S. Pat. No. 4,214,020 to Ward et al (1980) describes a novel method for coating the exteriors of a bundle of hollow-fiber semipermeable membranes for use in fluid separations. Typical polymers coated are polysulfones, polystyrenes, polycarbonates, cellulosic polymers, polyamides and polyimides. Numerous depositable materials are listed, see col. 10, lines 55-col. 12, for example, poly(epichlorhydrin) or polyamides.
U.S. Pat. No. 4,239,714 to Sparks et al (1980) describes a method of modifying the pore size distribution of a microporous separation media so as to provide it with sharp upper cut-off of a pre-selected molecular size. This is accomplished by effectively blocking the entrances to all of the pores of the separation media larger than a pre-selected molecular size constituting the desired cut-off, but leaving unchanged the smaller pores. The separation media may be in the form of polymeric membranes, e.g. cellulose acetate, cellulose nitrate, polycarbonates, polyolefins, polyacrylics, and polysulfones. The foregoing is accomplished by filling the pores of the membrane with a volatile liquid and then evaporating the liquid to form voids at the entrances to the pores. A concentrated solution of a cross-linkable or polymerizable pore blocking agent, such as protein, enzyme, or polymeric materials is then applied to the surface of the membrane.
U.S. Pat. No. 4,250,029 to Kiser et al (1981) describes coated membranes having two or more external coatings of polyelectrolytes with at least one oppositely charged adjacent pair separated by a layer of material which is substantially charge neutralized. Kiser et al is primarily directed to the use of charged membranes to repel ions and thereby prevent passage through the membrane pores. The coated membranes are described as ordinary semi-permeable membranes used for ultrafiltration, reverse osmosis, electrodialysis or other filtration processes. A microscopic observation of the coated membranes shows microscopic hills and valleys of polyelectrolyte coating formed on the original external smooth skin of the membrane. The membranes are particularly useful for deionizing aqueous solutions. Preferred membranes are organic polymeric membranes used for ultra-filtration and reverse osmosis processes, e.g., polyimide, polysulfone, aliphatic and aromatic nylons, polyamides, etc. Preferred membranes are anisotropic hollow fiber membranes having an apparent pore diameter of from about 21 to about 480 angstroms.
Charge modified membranes are disclosed in U.S. Ser. No. 358,822 of Ostreicher filed May 9, 1973, now abandoned (corresponding to Japanese Pat. No. 923649 and French Pat. No. 74 15733). As disclosed therein, an isotropic cellulose mixed ester membrane, was treated with a cationic colloidal melamineformaldehyde resin to provide charge functionality. The membrane achieved only marginal charge modification. Additionally, the membrane was discolored and embrittled by the treatment, extractables exceeded desirable limits for certain critical applications, and the membrane was not thermally sanitizable or sterilizable. Ostreicher also suggests such treatment for the nylon membranes prepared by the methods described in U.S. Pat. No. 2,783,894 to Lovell (1957) and U.S. Pat. No. 3,408,315 to Paine (1968). It has been demonstrated that nylon microporous membranes treated according to Ostreicher would also demonstrate marginal charge modification, high extractables and/or inability to be thermally sanitizable or sterilizable.
Of additional interest are the following U.S. Pat. Nos.